Characterization of the Kremen-binding Site on Dkk1 and Elucidation of the Role of Kremen in Dkk-mediated Wnt Antagonism

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 May 27

PMID 18502762

Citations 50

Authors

Ke Wang

Yazhou Zhang

Xiaofeng Li

Lijun Chen

He Wang

Jianguo Wu

Jie Zheng

Dianqing Wu

Affiliations

Soon will be listed here.

Abstract

Wnt signaling is involved in a wide range of developmental, physiological, and pathophysiological processes and is negatively regulated by Dickkopf1 (Dkk1). Dkk1 has been shown to bind to two transmembrane proteins, the low density lipoprotein receptor-related proteins (LRP) 5/6 and Kremen. Here, we show that Dkk1 residues Arg(197), Ser(198), and Lys(232) are specifically involved in its binding to Kremen rather than to LRP6. These residues are localized at a surface that is at the opposite side of the LRP6-binding surface based on a three-dimensional structure of Dkk1 deduced from that of Dkk2. We were surprised to find that the Dkk1 mutants carrying a mutation at Arg(197), Ser(198), or Lys(232), the key Kremen-binding residues, could antagonize Wnt signaling as well as the wild-type Dkk1. These mutations only affected their ability to antagonize Wnt signaling when both LRP6 and Kremen were coexpressed. These results suggest that Kremen may not be essential for Dkk1-mediated Wnt antagonism and that Kremen may only play a role when cells express a high level of LRP5/6.

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References

Monaghan A, Kioschis P, Wu W, Zuniga A, Bock D, Poustka A . Dickkopf genes are co-ordinately expressed in mesodermal lineages. Mech Dev. 1999; 87(1-2):45-56. DOI: 10.1016/s0925-4773(99)00138-0. View

Brott B, Sokol S . Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins. Mol Cell Biol. 2002; 22(17):6100-10. PMC: 133995. DOI: 10.1128/MCB.22.17.6100-6110.2002. View

Wodarz A, Nusse R . Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1999; 14:59-88. DOI: 10.1146/annurev.cellbio.14.1.59. View

Moon R, Kimelman D . From cortical rotation to organizer gene expression: toward a molecular explanation of axis specification in Xenopus. Bioessays. 1998; 20(7):536-45. DOI: 10.1002/(SICI)1521-1878(199807)20:7<536::AID-BIES4>3.0.CO;2-I. View

Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler B . Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 2002; 417(6889):664-7. DOI: 10.1038/nature756. View

Glinka A, Wu W, Delius H, Monaghan A, Blumenstock C, Niehrs C . Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998; 391(6665):357-62. DOI: 10.1038/34848. View

Logan C, Nusse R . The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004; 20:781-810. DOI: 10.1146/annurev.cellbio.20.010403.113126. View

Li L, Yuan H, Xie W, Mao J, Caruso A, McMahon A . Dishevelled proteins lead to two signaling pathways. Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells. J Biol Chem. 1998; 274(1):129-34. DOI: 10.1074/jbc.274.1.129. View

Clevers H . Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127(3):469-80. DOI: 10.1016/j.cell.2006.10.018. View

10.

Moon R, Kohn A, De Ferrari G, Kaykas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004; 5(9):691-701. DOI: 10.1038/nrg1427. View

11.

Li L, Mao J, Sun L, Liu W, Wu D . Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J Biol Chem. 2001; 277(8):5977-81. DOI: 10.1074/jbc.M111131200. View

12.

Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A . LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 2001; 411(6835):321-5. DOI: 10.1038/35077108. View

13.

Peifer M, Polakis P . Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. Science. 2000; 287(5458):1606-9. DOI: 10.1126/science.287.5458.1606. View

14.

He X, Semenov M, Tamai K, Zeng X . LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004; 131(8):1663-77. DOI: 10.1242/dev.01117. View

15.

Li L, Yuan H, Weaver C, Mao J, Farr 3rd G, Sussman D . Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J. 1999; 18(15):4233-40. PMC: 1171499. DOI: 10.1093/emboj/18.15.4233. View

16.

Semenov M, Tamai K, Brott B, Kuhl M, Sokol S, He X . Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol. 2001; 11(12):951-61. DOI: 10.1016/s0960-9822(01)00290-1. View

17.

Zhang Y, Wang Y, Li X, Zhang J, Mao J, Li Z . The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol Cell Biol. 2004; 24(11):4677-84. PMC: 416395. DOI: 10.1128/MCB.24.11.4677-4684.2004. View

18.

Niehrs C . Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene. 2006; 25(57):7469-81. DOI: 10.1038/sj.onc.1210054. View

19.

Reya T, Clevers H . Wnt signalling in stem cells and cancer. Nature. 2005; 434(7035):843-50. DOI: 10.1038/nature03319. View

20.

Bafico A, Liu G, Yaniv A, Gazit A, Aaronson S . Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol. 2001; 3(7):683-6. DOI: 10.1038/35083081. View